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Activation, Caspase 8 pathway leads to Cell injury/death
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
After recruitment, dimerization and activation of Caspase8, the active caspase will clear executioner caspases (3,6,7) or activate the intrinsic apoptotic pathway via BID. (McIlwain et al. 2015)
Evidence Collection Strategy
Evidence Supporting this KER
It has been well established that caspase activation leads to cell death. In the caspase 8 pathway, the TRADD adaptor protein recruits FADD and forms a complex together with pro-caspase 8. Then caspase 8 can directly activate caspase-3, -6, or -7, which leads to apoptosis. Furthermore, Caspase8 can also splice Bid to tBid which promotes disruption of the membrane of mitochondria. Cytochrome C will be released and forms an apoptosome with followed by activation of Caspase 9 and Apaf1. These can stimulate procaspases 3,6,7 which can induce apoptosis. (Murphy 2012; Melino & Vaux 2010)
Uncertainties and Inconsistencies
Hepatocellular deletion of Caspase 8 in mice show less apoptosis after DCC treatment (model hepatocholestasis)(Chaudhary et al. 2013)
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
McIlwain, D.R., Berger, T. & Mak, T.W., 2015. Caspase Functions in Cell Death and Disease: Figure 1. Cold Spring Harbor Perspectives in Biology, 7(4), p.a026716. Available at: http://cshperspectives.cshlp.org/lookup/doi/10.1101/cshperspect.a026716.
Melino, G. & Vaux, D., 2010. Cell Death G. Melino & D. Vaux, eds.,
Murphy, K., 2012. Jayneway’s Immunology 8th ed.,
Manns, M.P. et al., 2010. 273 Short Term Safety, Tolerability, Pharmacokinetics and Preliminary Activity of Gs-9450, a Selective Caspase Inhibitor, in Patients With Chronic Hcv Infection. Journal of Hepatology, 52, pp.S114–S115. Available at: http://linkinghub.elsevier.com/retrieve/pii/S0168827810602759.
Liedtke, C. et al., 2011. Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology, 141(6), pp.2176–2187. Available at: http://dx.doi.org/10.1053/j.gastro.2011.08.037.
Chaudhary, K. et al., 2013. Caspase 8 differentially controls hepatocytes and non-parenchymal liver cells during chronic cholestatic liver injury in mice. Journal of Hepatology, 59(6), pp.1292–1298. Available at: http://dx.doi.org/10.1016/j.jhep.2013.07.026.